There are few animal models available for the study of hepatitis C (HCV) infection so that further understanding of the pathogenesis of liver disease associated with this infection must rely in part on studies in humans. We have the unique opportunity to examine the influence of immune response on the natural history and pathogenesis of this disease by studying three patient populations with HCV infection; liver transplant patients who have impaired T cell function, patients with common variable immunodeficiency who have impaired humoral immunity and patient with intact immune responses. Our hypotheses is that the natural history of disease differs in these three groups, and that progressive liver disease occurs more frequently in immunocompromised than in immunocompetent patients. Moreover, we propose that the effect of immune deficiency is independent of other factors which may influence disease progression, such as viral genotype and level of viral replication. Our secondary hypothesis is that viral diversity is central to the mechanism by which immune response influences disease progression. Using our three patient groups. we will examine the relationship between immune response and viral diversity, which will be measured indirectly by single stranded conformational polymorphism and directly by analysis of the sequence variation in the envelope region of HCV over time. The immune response could influence viral divergence either by selecting for or by inhibiting viral diversity. Support for the former hypothesis would be provided by finding that the rate of viral mutation is higher in immunocompetent than in immunocompromised patients. Support for the latter hypothesis would be provided by finding that the rate of viral mutation is lower in immunocompetent that in immunocompromised patients. In order to examine further the mechanism by which humoral immunity is associated with viral diversity, we will determine the time course of emergence of viral species and the production of antibodies specific for these viral isolates. Since viral diversity could influence disease progression independent of host immunity, we will examine directly the relationship between diversity and disease progression. Elucidation of the mechanisms by which HCV causes progressive disease is essential for improved understanding of the pathogenesis of disease as will as for the identification of patients at risk for serious consequences. Once identified, these patients will be the focus of intensive measures, both preventative and therapeutic, aimed at arresting progressive liver damage.